1. The helicase HAGE prevents interferon-α-induced PML expression in ABCB5+ malignant melanoma-initiating cells by promoting the expression of SOCS1
- Author
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Alan Graham Pockley, Tarik Regad, Robert C. Rees, Amanda K. Miles, Murrium Ahmad, Magdalena Elżbieta Buczek, and Morgan G. Mathieu
- Subjects
Cancer Research ,Small interfering RNA ,Skin Neoplasms ,Time Factors ,Suppressor of Cytokine Signaling Proteins ,Mice, SCID ,Promyelocytic Leukemia Protein ,DEAD-box RNA Helicases ,Mice ,Mice, Inbred NOD ,SOCS1 ,Phosphorylation ,Regulation of gene expression ,DDX43 ,biology ,ABCB5 ,Nuclear Proteins ,Neoplasm Proteins ,Tumor Burden ,Gene Expression Regulation, Neoplastic ,STAT Transcription Factors ,MMIC ,Neoplastic Stem Cells ,RNA Interference ,Original Article ,Stem cell ,Signal Transduction ,ATP Binding Cassette Transporter, Subfamily B ,Immunology ,Antineoplastic Agents ,Transfection ,Suppressor of cytokine signalling ,Gene Expression Regulation, Enzymologic ,Cellular and Molecular Neuroscience ,Promyelocytic leukemia protein ,Suppressor of Cytokine Signaling 1 Protein ,interferon-α ,Cancer stem cell ,Cell Line, Tumor ,Spheroids, Cellular ,melanoma ,Animals ,Humans ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,RNA, Messenger ,Cell Proliferation ,TYK2 Kinase ,PML ,Suppressor of cytokine signaling 1 ,Tumor Suppressor Proteins ,Ubiquitination ,Interferon-alpha ,Cell Biology ,Janus Kinase 1 ,Drug Resistance, Neoplasm ,biology.protein ,Cancer research ,Transcription Factors - Abstract
The tumour suppressor PML (promyelocytic leukaemia protein) regulates several cellular pathways involving cell growth, apoptosis, differentiation and senescence. PML also has an important role in the regulation of stem cell proliferation and differentiation. Here, we show the involvement of the helicase HAGE in the transcriptional repression of PML expression in ABCB5+ malignant melanoma-initiating cells (ABCB5+ MMICs), a population of cancer stem cells which are responsible for melanoma growth, progression and resistance to drug-based therapy. HAGE prevents PML gene expression by inhibiting the activation of the JAK–STAT (janus kinase–signal transducers and activators of transcription) pathway in a mechanism which implicates the suppressor of cytokine signalling 1 (SOCS1). Knockdown of HAGE led to a significant decrease in SOCS1 protein expression, activation of the JAK–STAT signalling cascade and a consequent increase of PML expression. To confirm that the reduction in SOCS1 expression was dependent on the HAGE helicase activity, we showed that SOCS1, effectively silenced by small interfering RNA, could be rescued by re-introduction of HAGE into cells lacking HAGE. Furthermore, we provide a mechanism by which HAGE promotes SOCS1 mRNA unwinding and protein expression in vitro. Finally, using a stem cell proliferation assay and tumour xenotransplantation assay in non-obese diabetic/severe combined immunodeficiency mice, we show that HAGE promotes MMICs-dependent tumour initiation and tumour growth by preventing the anti-proliferative effects of interferon-α (IFNα). Our results suggest that the helicase HAGE has a key role in the resistance of ABCB5+ MMICs to IFNα treatment and that cancer therapies targeting HAGE may have broad implications for the treatment of malignant melanoma.
- Published
- 2014